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- Title
Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT<sub>1A</sub> receptor mechanisms in vivo.
- Authors
Sullivan, Nicole; Crane, James; Damjanoska, Katerina; Carrasco, Gonzalo; D'Souza, Deborah; Garcia, Francisca; Kar, Louis
- Abstract
Tandospirone, an azapirone, is a selective serotonin1A (5-HT1A) receptor agonist. The effects of tandospirone on plasma hormones and on mitogen-activated protein (MAP) kinase activity in the brain of male rats were studied. Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin, adrenocorticotropin (ACTH), corticosterone, and prolactin. The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin, ACTH, and prolactin levels was 1.0 mg/kg (s.c.), while the minimal dose for corticosterone release was 3.0 mg/kg (s.c.). The ED50 of tandospirone was 1.3 mg/kg for oxytocin, 1.2 mg/kg for ACTH, 3.0 mg/kg for corticosterone, and 0.24 mg/kg for prolactin. Pretreatment with the specific 5-HT1A receptor antagonist WAY 100,635 (0.3 mg/kg, s.c.) completely blocked the effects of tandospirone on plasma levels of oxytocin, ACTH, and corticosterone but shifted the dose-response curve for prolactin to the right. Tandospirone injection (10 mg/kg, s.c.) stimulated the MAP kinase signaling cascade, specifically the phosphorylation of p42/44 extracellular signal-regulated kinase (ERK). Western blot analysis revealed a significant increase in phosphorylated ERK (p-ERK) levels in the hypothalamic paraventricular nucleus (PVN) as well as the dorsal raphé nucleus 5 min following tandospirone injection. These increases were blocked by pretreatment with WAY 100,635 (0.3 mg/kg). The results are the first evidence that systemic 5-HT1A receptor agonist administration produces a rapid increase in p-ERK levels in vivo, providing further insight into the signaling mechanisms of the 5-HT1A receptor.
- Subjects
SEROTONIN; PROTEINS; OXYTOCIN; LABORATORY rats; PLASMA gases; MITOGENS; CORTICOSTERONE
- Publication
Naunyn-Schmiedeberg's Archives of Pharmacology, 2005, Vol 371, Issue 1, p18
- ISSN
0028-1298
- Publication type
Article
- DOI
10.1007/s00210-004-1005-7